FR2570377A1 - AROMATIC HETEROCYCLIC DERIVATIVES AND THEIR APPLICATION IN THE THERAPEUTIC AND COSMETIC FIELDS - Google Patents

Abstract

AROMATIC HETEROCYCLIC COMPOUNDS OF FORMULA: (CF DRAWING IN BOPI) IN WHICH: R IS (I) -CH, (II) -CHOH OR (III) -CR R BEING H, -OR, R BEING H, ALKYL (1-20C ) OR MONO OR POLYHYHYDROXYALKYL

Description

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  The subject of the present invention is novel hetero derivatives.

  cyclic aromatic compounds, their process of preparation and their use in

  human or veterinary therapeutic and in cosmetics.

  These novel heterocyclic derivatives have a biological profile which is related to the compounds known under the name "retinoid" whose most well-known representatives are trans and cis-retinolic acids.

  (tretinoin and isotretinoin) and etretinate.

  Compared with retinols, the aromatic heterocyclic compounds according to the invention, because of their structure, have a better stability to light and oxygen and, moreover, a reinforced activity in the topical and systemic treatment of dermatological disorders related to a disorder of keratinization (differentiation-proliferation) and dermatological conditions, or others, with an inflammatory and / or immunoallergic component as well as an anti-tumor activity. In addition, these products can be used in the treatment of atopy, be it cutaneous or respiratory. These compounds also find application in the field

  Ophthalmological, especially for the treatment of corneopathies.

  In view of their chemical structure and their activity, the aromatic heterocyclic compounds according to the invention will be designated

  hereinafter referred to as "hetero-differentials".

  The heterodiffers according to the invention may be represented by the following general formula: embedded image

R2

  in which: R1 represents: (i) -CH3 (ii) -CH2OH (iii) -CR3 represents a hydrogen atom, the radical -OR4, R4 representing a hydrogen atom, an alkyl radical having from 1 to 20 carbon atoms, a mono-or polyhydroxyalkyl radical or R3 represents the radical - N 'and r "representing a hydrogen atom, a lower alkyl radical or taken together form a heterocycle, -R2 represents a hydrogen atom; hydrogen or the -CH3 radical, Ar represents an aromatic radical corresponding to one of the following formulas: (a) CH CH

()IT)

CH CH

C H3 3

* 15 (B)

  Z being 0 or S (c) R (C) R 5 R 5 representing a lower alkyl radical and (d)

R 60 C (D)

R60

  R 7 R 6 representing a hydrogen atom or an alkyl radical having 1 to 10 carbon atoms and R 7 representing a branched alkyl radical having 4

  to 12 carbon atoms or a cycloalkyl radical.

  Y represents CH or a nitrogen atom, and X represents an oxygen atom, a sulfur atom or the radical -N R8, R8 representing a hydrogen atom, a lower alkyl radical or a lower alkoxycarbonyl radical, -3 subject, on the one hand, that when Y represents CH and X represents an oxygen or sulfur atom, Ar is other than a radical of formula (C) in which R5 = -CH3 and on the other hand only when Y represents a nitrogen atom and X represents an oxygen atom, Ar is different from a radical of formula (C) or of formula (D) -in which R 6 represents an alkyl radical having from 1 to 4 carbon atoms and R7 represents a branched alkyl radical

having from 4 to 12 carbon atoms.

  By lower alkyl radical is meant a radical having from 1 to 6 carbon atoms, in particular a methyl, ethyl or isopropyl radical,

butyl and tert-butyl.

  By monohydroxyalkyl radical, we must mean a radical having 2

  or 3 carbon atoms, in particular a 2-hydroxyethyl radical, and 2 hydroxypropyl

  pyle. Polyhydroxyalkyl radical means a radical derived from

  glycerol, pentaerythritol or mannitol.

  By lower alkoxycarbonyl radical is meant a radical having an alkyl chain namified or not, of 1 to 4 carbon atoms. Among the lower alkoxycarbonyl radicals that may be mentioned include: methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl and tert-butoxy radicals;

carbonyl.

  When the radicals r 'and r "taken together form a heterocycle,

  this may be a piperidino, piperazino, morpholino or pyrrolidine radical

  dino. When the radical R7 represents a cycloalkyl radical, this

  is preferably a cyclohexyl, 1-methylcyclohexyl or adamantyl radical.

  According to a particular embodiment, the hetero-differentiators according to the invention have the following general formula:

CH3 CH3

(He)

CH C

  in which: R1 represents -CH20H or -C-R3 represents R4 representing -OR4 or -N / R4-R4 representing a hydrogen atom, a radical -CH3 or -CH2CH20H r 'and r "identical or different representing a hydrogen atom, a lower alkyl radical or taken together form a morpholino ring Y represents CH or a nitrogen atom and X represents a sulfur atom, an oxygen atom or N-R8, R8

  being a hydrogen atom, the -CH3 or -CO2tert-butyl radical.

CH3 X C-0-R

30

  Wherein R4 is hydrogen or -CH3 Y is CH or N, and X is sulfur, oxygen, or N-R8, R8

  being a hydrogen atom or the radical -CO2 tert-butyl.

y (IV) C-O-R R O

R60

  Wherein: R4 represents a hydrogen atom or a radical -CH3 R6 represents the radical -CH3 or C1H21 R7 represents the tert-butyl radical, dimethyl-l, 1 decyl or adamantyl Y represents CH or a nitrogen atom and X represents a sulfur atom, an oxygen atom or N-R8, R8

being a hydrogen atom.

  Among the preferred heteroparines of formula (I), mention may be made in particular of: methyl 2- (p-tert-butylphenyl) -6-benzo (b) thiophenecarboxylate, 2- (p-tert) acid; butylphenyl) -6benzo (b) thiophenecarboxylic acid,

  2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -6-benzo (b) thiophene-

Methyl carboxylate,

  2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -6-benzo (b) -

  thiophenecarboxylic acid, methyl 2- (p-tert-butylphenyl) benzo (b) furancecarboxylate, 2- (p-tert-butylphenyl) -benzo (b) furancarboxylic acid,

  2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -6-benzo (b) furan

methyl carboxylate,

  2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -6-benzo (b) -

  furanecarboxylic acid, methyl 1-tert-butoxycarbonyl-2- (p-tert-butylphenyl) -6-indolecarboxylate - 2- (p-tert-butylphenyl) -6-indolecarboxylic acid,

  1-tert-butoxycarbonyl-2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-

  methyl naphthyl) -6-indolecarboxylate, methyl 2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -6-indolecarboxylate,

  2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -

6-indole,

  1-methyl-2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -indole-

methyl carboxylate,

  1-methyl-2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -6-

  indolecarboxylic acid, methyl 2- (p-tert-butylphenyl) -5-benzimidazole carboxylate, 2- (p-tert-butylphenyl) -5-benzimidazole carboxylic acid,

  2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -benzimidazole

methyl carboxylate,

  2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) benzimidazole acid;

carboxylic acid,

  2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -6-benzoxazole

methyl carboxylate,

  2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -6-benzoxazole acid

carboxylic acid,

  the morpholide of 2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)

tyl) -6-benzoxazole carboxylic acid,

  2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) ethylamide

tyl) -6-benzoxazole carboxylic acid,

  2-hydroxyethyl ester of 2- (5,6,7,8-tetrahydro-5,5,8,8tetrahydrate)

  methyl-2-naphthyl) -6-benzoxazole carboxylic acid, 2- (5,6,7,8-tetrahydro-5-5,8- (8-tetramethyl-2-naphthyl) -6-benzoxazolyl-6-methyl alcohol ,

  2- [3- (1-adamantyl) -4-methoxyphenyl] -benzic acid methyl ester

carboxylic midazole,

  2- [3- (1-adamantyl) -4-methoxyphenyl] -6-benzoic acid methyl ester

  xazole carboxylic acid, 2- [3- (1-adamantyl) -4-methoxyphenyl] -6-benzoxazole carboxylic acid,

  2- [3- (1-adamantyl) -4-decyloxyphenyl] -benzyl methyl ester

  zoxazole carboxylic acid, 2-13- (1-adamantyl) -4-decyloxyphenyl] -6-benzoxazole carboxylic acid,

  2- [3- (1-adamantyl) -4-methoxyphenyl] -6-benzoic acid methyl ester

(b) carboxylic furan,

  2- [3- (1-adamantyl) -4-methoxyphenyl-6-benzo (b) furan carboxy-

lic,

  2- (3- (1-adamantyl) -4-methoxyphenyl] -6-benzoic acid methyl ester

(b) carboxylic thiophene,

  2- [3- (1-adamantyl) -4-methoxyphenyl] -6-benzo (b) thiophene carboxylic acid

lic,

  2- (3-tert-butyl-4-methoxyphenyl) -6benzo (b) - methyl ester

  carboxylic furan, - 2- (3-tert-butyl-4-methoxyphenyl) -6benzo (b) furan carboxylic acid, - 2- [3- (1,1-dimethyl-decyl) - methyl ester methoxyphenyl] -6-benzo (b) furan carboxylic acid, 2- [3- (1,1-dimethyldecyl) -4-methoxyphenyl] -6-benzo (b) furan carboxylic acid, 3- (1-adamantyl) -4-methoxyphenyl] -5-benzimidazole carboxylic acid,

  2- [3- (1-adamantyl-4-hydroxyphenyl) -5benzic acid methyl ester

carboxylic midazole,

  2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl) methyl ester

  2-naphthyl) -6-benzothiazole carboxylic acid,

  2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -6-benzothiazole acid;

carboxylic acid,

  and 2- (4,4-dimethyl-2-3-dihydro-1-benzopyran) methyl ester

6-yl) -5-benzimidazole carboxylic acid.

  Various synthetic methods can be envisaged for obtaining compounds of formula (I). Among these methods, the following can be mentioned in particular: A) First method (Scheme I)

  This method involves reacting a carboxylic acid derivative

  aromatic compound of formula (1) on an aromatic carboxylic acid ester of formula (2) bearing an amino radical in the 4-position and an amino radical,

hydroxy or thio in position 3.

  This method is particularly preferred when in

  compounds of formula (I) the radical Y represents a nitrogen atom.

Scheme I] 0

Ar / Q ±

H OR4-

(l) R2 (2) 0

NOT

Ar OR

R O

(3)

  Q = OH or Cl X = NH, O or SB) Second method (Scheme II) This method comprises reacting the aromatic carboxylic acid derivative of formula (1) with an aromatic carboxylic acid ester of formula (4) carrying in position 4 a methyl radical and an amino, hydroxy or thio group in the 3-position. The intermediate compound obtained (5) is then

  bromated to the methylated bromo derivative at position 4 (6).

  After reacting a triaryl or trialkylphosphine, a triaryl or trialkylphosphite, or an arylphosphine oxide compound (7) is obtained which is then cyclized compound of formula (8) This method is particularly preferred when in the

  compounds of formula (I) Y represents the radical CH.

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Scheme II CH Ar Q 0

CR3 O

1 ArI X OF

+

R = x

HX 4

(1) R2 (4) (5)

  BrCH2 (7). - -b _ Ar xo; k <xOR4

(6) R2

A1 = CH2o OR4 J 0

(Z) R

  (7) pasged _cmos_ 7) acmos_8_etefetueenpésne_'nebs Ar

3 OR4

0

(3) R2

  Q = OH or Cl X = NH, O or S A1 = -e (V) 3 Br-V being alkyl or aryl or - - (W) 2, W being aryl, alkoxy or aryloxy or - - According to this latter method, the cyclization reaction, that is to say the passage of the compound (7) to the compound (8), is carried out in the presence of a base which may be a hydroxide or a carbonate of alkali metal for example lithium hydroxide or potassium carbonate, an alkali metal hydride for example sodium hydride, an alkali metal alkoxide for example sodium methoxide or potassium tert-butoxide, a tertiary amine for example triethylamine, di-isopropylethylamine or diazabicycloundecene (DBU) or

  alkali metal amide, for example sodium amide or diisopropyl

  Lithium chloride. The temperature of the reaction is between -10.degree. C. and + 150.degree. C. and a dipolar aprotic solvent (dimethylsulfoxide or dimethylformamide), an alcohol, an ether (dioxane or

  tetrahydrofuran). The reaction is advantageously carried out in the tetra-

  hydrofuran (THF) between 0 C and 80 C using triethylamine or DBU

as a basis.

  The bromination reaction, that is to say, the preparation of the compounds of formula (A) is carried out in the presence of N-bromosuccinimide in the previously dried benzene or carbon tetrachloride, the temperature preferably being between 70.degree. C and 90 C, the radical initiator being

  preferably benzoyl peroxide.

  The acylation reaction followed by desiccant cyclization according to Scheme I and the acylation reaction according to Scheme II is carried out in a conventional manner. When X represents an NH group, the reaction is advantageously carried out using a compound of formula (1) in the form of

  acid chloride (Q = Cl) in the presence of a tertiary amine.

  The desiccant cyclization reaction according to scheme I is preferably carried out by means of an acid catalyst, for example acid

  p-toluene sulfonic acid at reflux of the solvent, preferably xylene.

  The esters obtained according to the methods described above can be converted in a conventional manner into various analogs which are the subject of the

  meanings (i) to (iii), radical R1.

  Thus the saponification of these esters gives the corresponding acids

  dent. These can be converted into acid chlorides which are then easily converted into amides. These amides can also be obtained by direct action of amines on the esters obtained above. The reduction of the esters, aldehydes or amides by a suitable reducing agent (for example

  Lithium Aluminohydride) allows access to the corresponding alcohols and amines.

  dent. When the compounds according to the invention are in the form of salts, they may be either salts of an alkali metal or alkaline earth metal or organic amines when the compounds of formula (I) are present in the form of salts.

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  free acid form, either salts of mineral or organic acids when the

  compounds of formula (I) are in free amine form.

  The compounds according to the invention have good to excellent activity in the inhibition test of ornithine decarboxylase in the naked rat after induction by "tape stripping". This test is accepted as a measure of

  the action of retinols on cell proliferation phenomena.

  These compounds are particularly suitable for treating

  dermatological conditions related to a disorder of keratinisation (differ-

  denial, proliferation) as well as dermatological or other affections, with an inflammatory and / or immunoallergic component, cutaneous or respiratory atopy, in particular: - acne vulgaris, comedoniennes or polymorphs, acnes

  senile solar, and medicated or professional acnes.

  - extensive and / or severe forms of psoriasis, and other

  disorders of keratinization, and in particular ichthyosis and ichthyosis

forms.

- Darier's disease.

  - palmoplantar keratoderma.

  - leukoplasias and leukoplasiform states, lichen planus.

  - all benign or malignant dermatological proliferations,

severe or extensive.

  - eczema - asthma They are also active for certain rheumatic diseases

  psoriatic arthritis as well as some ophthalmic problems.

related to the cornea.

  The present invention therefore also relates to a medicinal product

  killed by at least one compound of formula (I) and / or a salt thereof as defined above.

  The present invention therefore also relates to a new composition

  medicinal product, intended in particular for the treatment of the

  mentioned, characterized in that it comprises, in a support

  pharmaceutical acceptable, at least one compound of formula (I).

  As has been previously indicated, the heterocyclic derivatives according to the invention have, compared to conventional retinoids, better stability to light and oxygen, this being essentially due to

  because they do not have an easily isomerizable double bond.

  The compounds according to the invention are generally administered at a

  daily dose of about 2 μg / kg to 2 mg / kg body weight.

  As the support for the compositions, any conventional support may be used, the active compound being either in the dissolved state or

  the state scattered in the vehicle.

  Administration may be enteral, parenteral, topical or ocular. Enterally, the drugs may be in the form of tablets, capsules, dragees, syrups, suspensions, solutions, powders, granules, emulsions. Parenterally, the compositions may be in the form of solutions or suspensions for

infusion or for injection.

  By topical route, the pharmaceutical compositions, based on the compounds according to the invention, are in the form of ointments, dyes,

  creams, ointments, powders, patches, soaked swabs,

  lotions, gels, sprays or suspensions. Compositions

  The topical formulations preferably contain from 0.0005 to about 5% by weight.

  weight of compound (s) of formula (I).

  These compositions topically can be presented in anhydrous form or in aqueous form according to the clinical indication. By route

  ocular, they are mainly eye drops.

  The compounds of formula (I) according to the invention also find a

  application in the cosmetics field, in particular in body hygiene.

  and hair and especially for acne, for hair regrowth, anti-hair loss, to fight against the greasy appearance of the skin or hair or in the treatment of the harmful effects of the sun, or to fight against

  the skin is physiologically dry.

  The present invention therefore also relates to a cosmetic composition containing, in an acceptable cosmetic support, at least one compound of formula (I), this composition being in particular in the form of a lotion,

gel, soap, shampoo or cream.

  The concentration of compound (s) of formula (I) in the compounds

  cosmetic compositions is between 0.0005 and 2% by weight and preferably

between 0.01 and 1% by weight.

  The medicinal and cosmetic compositions according to the invention

  may contain inert additives or even pharmacodynamically or cosmetically

  active ingredients and in particular: hydrating agents such as thiamorpho-

  linone and its derivatives or urea, antiseborrhoeic agents, such as

  S-carboxymethyl cysteine, S-benzyl-cysteamine and their derivatives, tioxo

  lone, anti-acne agents, antibiotics, such as erythromycin and

  its esters, neomycin, tetracyclines, polymethylenes-4,5 isothiazines

  zolinones-3; agents that promote hair regrowth, such as

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  xidil "(2,4-diamino-4, 6-piperidino-3-pyrimidine-3-oxide) and its derivatives;

  thraline and its derivatives; Diazoxide (3-chloromethyl-1,2,4-benzothiadiazine-1,1-dioxide), Phenyl (2,4-diphenyl-1,5-imidazolidinedione-2,4) and iodide

  of oxapropanium; Steroidal and non-steroidal anti-inflammatory agents

  dian; carotenols and, especially, -carotene; anti-agents

  psoriatic agents such as anthralin and its derivatives, eicosatetra-

  5, 8, 11, 14 and -triynotropic 5, 8, 11, their esters and amides.

  The compositions according to the invention may also contain flavor enhancers, preservatives, agents and the like.

  stabilizers, moisture regulating agents, pH regulating agents.

  osmotic pressure modifiers, emulsifiers,

  UV-A and UV-B filters, antioxidants such as o- (tocopherol, butyl)

  droxyanisole or butylhydroxy toluene.

  Several examples of the preparation of the active compounds of formula are given by way of illustration and without any limiting character.

  (I) according to the invention as well as examples of compositions containing them.

EXAMPLE 1

  2- (p-tert-Butylphenyl) -6-benzo (b) thiophenecarboxylate methyl.

  a) Methyl 3- (p-tert-Butylbenzoylthio) -4-methylbenzoate.

  In 20 ml of dry TUF, 1.80 g (10 mmol) of

  Methyl 3-mercapto-4-methylbenzoate, 1.11 g (1.5 ml, 11 mmol) of triethyl

  lamine and 2.20 g (11 mmol) of p-tert-butylbenzoyl chloride. It is stirred for 2 hours at 20 ° C., poured into water (100 ml) and extracted with dichloromethane (3 × 100 ml). The organic phase is dried and evaporated. It is then purified by passage over a short silica column (× 10 cm), eluting with a mixture of dichloromethane (50%) and hexane (50%). The product having a Rf = 0.35 (eluent: dichloromethane) is collected. The solvents are evaporated to give methyl 3- (p-tert-Butylbenzoylthio) -4-methylbenzoate (3.08 g,

90%).

  b) methyl 4-Bromomethyl-3- (p-tert-butylbenzoylthio) benzoate.

  2.80 g of the ester obtained in Example 1 (a) are dissolved in 20 ml of tetra-

  Dry carbon chloride, reflux. 20 mg of benzoyl peroxide and, in portions, 1.45 g (8.15 mmol) of N-bromosuccinimide are added. After refluxing for 10 hours, 0.145 g (0.8 mmol) of N-bromosuccinimide are added and the mixture is refluxed for a further 4 hours. The solvents are evaporated and the residue is roughly purified by passing through a short column of silica (5x10 cm) eluting with dichloromethane. There is thus obtained a mixture of 3 products having Rf = 0.35; 0.40; 0.45. (eluent: dichloromethane). These products are, by -13 -

- 13 - 2570377

  order of decreasing polarity: the starting material, the monobrominated product and the dibromed product. The latter is removed by chromatography ("Waters" Prep 500, silica column, eluent: mixture of dichloromethane (50%) and hexane

(50%)

  An oil (3.20 g) containing about 80% of ester is thus obtained

  desired and about 20% of starting material.

  c) Methyl 2- (p-tert-butylphenyl) -6-benzo (b) thiophenecarboxylate.

  In 20 ml of THF, 3.10 g of the mixture obtained in Example 1 (b) and 1.85 g (7 mmol) of triphenylphosphine are dissolved. Refluxed under nitrogen for 4 hours, then cooled and added dropwise 1.06 g (7 mmol) of diazabicycloundecene (DBU). When adding each drop, the transient appearance of a dark yellow color is observed. At the end of the addition, a slight precipitate is observed. It is heated at 50 ° C. for 15 minutes, poured into water (100 ml), extracted with dichloromethane (3 × 100 ml), dried and the solvents evaporated. The desired product is obtained by chromatography (silica column, eluent: mixture of dichloromethane (20%) and hexane (80%).

* obtained is recrystallized from hexane. This yields 2- (p-tertbutyl-

  methyl phenyl) -6-benzo (b) thiophenecarboxylate (1.60 g, 62% from

the ester obtained in 1 (a)).

  F: 155 C; Rf = 0.70 (eluent: mixture of dichloromethane (20%) and hexane

(80 Z)).

EXAMPLE 2

  2- (p-tert-Butyl-phenyl) -6-benzo (b) thiophenecarboxylic acid 1.2 g (3.7 mmol) of the ester obtained in Example 1 (c) are suspended in 100 ml 2N sodium hydroxide solution in methanol. We heat 4 hours

  reflux, poured into water (100 ml), acidified to pH 0 with hydrochloric acid

  concentrated drique, extracted with ethyl ether (3x100 ml), dried and evaporated. The solid obtained is recrystallized from acetonitrile. We obtain

  thus 2- (p-tert-Butylphenyl) -6-benzo (b) thiophenecarboxylic acid.

(1.05 g, 91%).

  F: 318 C. Rf = 0.7 (eluent: mixture of dichloromethane (80%) and methanol

(20%)).

EXAMPLE 3

  2- (5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -6-benzo (b)

methyl thiophenecarboxylate.

  a) 4-Methyl-3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoyl)

thio) methyl benzoate.

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  In a similar manner to Example 1 (a), starting from 1.83 g (10 mmol) of methyl 3-mercapto-4-methylbenzoate, 1.5 ml of triethylamine and

  2.76 g (11 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-chloride

  naphthoyl, there is obtained 4-methyl-3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl)

  Methyl 2-naphthoylthio) benzoate. (3.50g, 88%)

  F: 120 ° C. Rf = 0.7 (using dichloromethane as eluent).

  b) 4-Bromomethyl-3- (5,6,7,8-tetrahydro- (5,5,8,8-tetramethyl-2-naphthoyl)

thio) methyl benzoate.

  In a manner analogous to Example 1 (b), starting from 3.30 g (8.3 mmol)

  of the ester obtained in Example 3 (a), 1.48 g (8.3 mmol) of N-bromosuccin

  nimide, and 20 mg of benzoyl peroxide, after chromatography ("Waters" prep 500, silica column, eluent: mixture of dichloromethane (60%) and hexane (40%)), a mixture containing about 10% product of

  90% of 4-bromomethyl-3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl)

  2-naphthoylthio) methyl benzoate. (2.50 g).

  c) In a manner analogous to Example 1 (c), starting from 2.40 g of the mixture obtained in 3 (b) and 1.6 g of triphenylphosphine, in 15 ml of THF, after reflux of 6 g, hours, a phosphonium salt that is immediately treated with 0.9ml of DBU. After treatment in a manner analogous to Example 1 (c)

  and after chromatography (silica column, eluent: mixture of dichloromethane

  30% thane and 70% heptane) gives 2- (5,6,7,8-tetrahydro-5,5,8,8-

  Methyl tetramethyl-2-naphthyl) -6-benzo (b) thiophenecarboxylate. (1.50g 50%

  from the ester obtained in 3a)).

  F: 170 C, Rf = 0.8 (eluent: dichloromethane)

EXAMPLE 4

  2- (5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -6-benzoic acid

(b) thiophene carboxylic acid.

  In a manner analogous to Example 2, starting with 1.10 g (2.9 mmol)

  the ester obtained in Example 3 (c), 2- (5,6,7,8-tetrahydro-

  5,8,8-tetramethyl-2-naphthyl) -6-benzo (b) thiophene carboxylic acid. (0.99 g, 93%) F: 297 ° C., Rf = 0.7 (eluent: mixture of dichloromethane (80%) and methanol

(20%)).

EXAMPLE 5

  2- (p-tert-Butylphenyl) -6-benzo (b) furancecarboxylate methyl.

  a) Methyl 3- (p-tert-Butylbenzoyloxy) -4-methylbenzoate.

  In a similar manner to Example 1 (a), from 3.30 g (20 mmol) of methyl 3-hydroxy-4-methylbenzoate, triethylamine (2.20 g, 22 mmol) and

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P-tert-butylbenzoyl chloride (3.90 g, 20 mmol) in 40 ml of THF,

  methyl 2- (p-tert-butylbenzoyloxy) -4-methyl benzoate is obtained. (5, 30g, 81Z)

  Rf 0.45 (eluent: ethyl ether (30%) and hexane (70%)).

  b) methyl 4-Bromomethyl-3- (p-tert-butylbenzoyloxy) benzoate.

  Analogously to Example 1 (b), from 1.60 g (Smmol) of the ester obtained in (a), 1.30 g of N-bromosuccinimide and benzoyl peroxide (10 mg), dissolved in 5 ml of carbon tetrachloride and refluxed under nitrogen for 20 minutes, after chromatography (HPLC, column "ZORBAX SIL", eluent mixture dichloromethane (80%) hexane (20%)), 4-bromomethyl-3 - (p-tert-butylbenzoyloxy) methyl benzoate. (0.94 g, 46 t) F: 107 C, Rf = 0.40 (eluent: mixture of ethyl ether (30%) and hexane

(70%)).

  c) Methyl 2- (p-tert-butylphenyl) -6-benzo (b) furancecarboxylate.

  In a similar manner to Example 1 (c), starting from 0.52 g (1.30 mmol) of ester obtained in Example 5 (b), and triphenylphosphine (0.40 g) in 2 ml of THF, After heating under reflux for 4 hours under nitrogen, then treatment with DBU (0.30 g) for 15 minutes at 20 ° C. and then 15 minutes under reflux, the crude desired ester is obtained. After purification (HPLC, "ZORBAX SIL" column, eluent: diisopropyl ether mixture (10%), heptane (90%)), methyl 2- (p-tert-butylphenyl) -6-benzo (b) furancecarboxylate is obtained. . (0.35g, 87%)

  F: 148 ° C, Rf = 0.55 (eluent: ethyl ether mixture (30%) heptane (70%)).

EXAMPLE 6

  2- (p-tert-Butylphenyl) -6-benzo (b) furancecarboxylic acid.

  0.30 g (lmmol) of ester obtained in Example 5 (c) are dissolved in 10 ml of ethanol. 2 ml of potassium hydroxide (5N) are added and the mixture is heated for 2 hours at 50 ° C. The precipitate obtained is dissolved by addition of water (30 ml) and 10 ml of hydrochloric acid (N) are added. Extracted with 150 ml of ethyl ether, washed with water to pH-6 and evaporated. A residue is obtained which is dried and dissolved

  in THF (20ml). On evaporation of THF, 2- (p-tert-) acid is obtained.

  butylphenyl) -6-benzo (b) furancarboxylic acid. (0.28 g, 98%) F: 294 C, RfO0, 60 (eluent: mixture of dichloromethane (80%) and methanol

(20 Z)).

EXAMPLE 7

  2- (5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -6-benzo (b) -

methyl furanecarboxylate.

  a) 5'-methoxycarbonyl-2'-methylphenyl-5,6,7,8-tetrahydro-5,5,8,8-tetrahydro-

methyl-2-naphthoate.

- 16-2570377

  Analogously to Example 5 (a), from 3.32 g (20 mmol) of methyl 3-hydroxy-4-methyl benzoate, and 5.51 g (22 mmol) of chloride, 6.7, 8 , -tetrahydro-5,5,8,8-tetramethyl-2-naphthoyl, the 5-methoxy

  2'-methylmethylphenyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoate

(7.10g, 93%).

  F: 159 C, Rfm0.6 (eluent: melted ethyl ether (50%), hexane (50%)).

  b) 2'-Bromomethyl-5'-methoxycarbonyl-phenyl 5,6,7,8-tetrahydro-5,5,8,8-

  tetramethyl-2-naphthoate. Analogously to Example 5 (b), from 1.33 g (3.5 mmol) of the ester obtained in 7 (a), there is obtained 2'-bromomethyl-5'-eithoxycarbonylphenyl, 6,7,8 -tetrahydro-5,5,8,8-tetramethyl-2-naphthoate (1.00 g, 62%).

  F: 119 C, Rf-0.4 (eluent: ethyl ether mixture (301), hexane (70Z)).

  c) In a manner analogous to Example 5 (c), starting from 0.76 g (1.66 mmol)

  of the ester obtained in 7 (b), 2- (5,6,7,8-tetrahydro-5,5,8,8-tetrahydro-

  methyl-2-naphthyl-6-benzo (b) furancecarboxylate methyl. (0.51g, 85Z).

  F: 112 C, Rf = 0.55 (eluent: ethyl ether (30%), heptane (70%)).

EXAMPLE 8

  2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -6-

benzo (b) furancecarboxylic.

  In a manner analogous to Example 6, 3.00 g (8.3 mol) of the ester obtained

  in 7 (c), are treated with 200ml of a sodium hydroxide solution in methanol (2N).

  After heating for 4 hours under reflux, the mixture is evaporated, poured into water (100%), acidified to pH 0 with concentrated hydrochloric acid, extracted with ether.

  (3xl00ml), dry and evaporate. The residue is recrystallized from acetonitrile.

  In this way, 2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-

  2-naphthyl) -6-benzo (b) furancarboxylic acid. (2.30g, 80Z).

  F: 280 ° C, Rf = 0.75 (eluent: ethyl ether).

EXAMPLE 9

  Methyl 1-tert-butoxycarbonyl-2- (p-tert-butylphenyl) -6-indolecarboxylate.

  a) Methyl 3- (p-tert-Butylbenzamido) -4-methylbenzoate.

  3.30 g (20 mmol) of methyl 3-amino-4-methyl benzoate dissolved in 40 ml of THF are treated at 0 ° C. with 3.9 g (20 mmol) of p-tertbutylbenzoyl chloride in the presence of 2.2 g (20 mmol). ) of triethylamine. After 2 hours, 100 ml of water are added, and the precipitate obtained is collected and washed with water (3 × 100 ml). We

  Vacuum dried and recrystallized from carbon tetrachloride.

  Thus 3- (p-tert-butylbenzamido) -4-methyl benzoate is obtained.

- 17 - 2570377

methyl. (5.70g, 88%)

  F: 193 C, Rf = 0.85 (eluent: ethyl ether).

  b) 3 [-N (tert-Butoxycarbonyl) -p-tert-butylbenzamido] 4-methyl benzoate

of methyl.

  0.97 g (3 mmol) of ester obtained in 9 (a) are dissolved in 5 ml of THF and 1 ml of DMF. 100 mg of sodium hydride (80% in oil, 3.3 mmol) is added

  and stirred for 1 hour. 0.72 g of dicarbonate of

  butylated and stirred for 2 hours at 20 ° C. It is then poured into water (100 ml), extracted with dichloromethane (3 × 50 ml), evaporated and dried. We recrystallize

  the residue obtained in cyclohexane. This yields 3- (tertbutoxycarboxyl)

  butyl-p-tert-butylbenzamido) -4-methyl benzoate. (1.10g, 86%).

  F: 153 C, Rf = 0.5 (eluent: ethyl ether mixture (5%), dichloromethane%)). c) 4-Bromomethyl-3- (tert-butoxycarbonyl-p-tert-butylbenzamido) benzoate

of methyl.

  4.30 g (10 mmol) of the ester obtained in 9 (b) are treated with 1.80 g (10 mmol) of N-bromo-succinimide and 20 mg of benzoyl peroxide for 2 hours.

  hours in carbon tetrachloride at reflux. 0.20g of Nbromo-

  succinimide and reflux for 1 hour. The solvent is evaporated and the mixture is filtered through a short column of silica (5 × 10 cm), using

  as eluent a mixture of chloroform (90%) and hexane (10%).

  After chromatography ("Waters" Prep 500, silica column, eluent: ethyl ether mixture (10%), dichloromethane (20%), hexane (70%)), 4-bromomethyl-3- (tert-butoxycarbonyl) is obtained. p-tert-butylbenzamido) benzoate

methyl. (3.60g, 71%).

  F: 135 C, Rf = 0.6 (eluent: dichloromethane).

  d) methyl 1-tert-butoxycarbonyl-2- (p-tert-butylphenyl) -6-indolecarboxylate. 3.30 g (6.5 mmol) of the ester obtained in 9 (c) are dissolved in 20 ml of THF. 2.05 g (7.8 mmol) of triphenylphosphine are added and the mixture is refluxed for 6 hours. It is cooled to 20 ° C. and 1.17 ml (7.8 mmol) of DBU is added. The mixture is refluxed for 30 minutes, poured into water (100 ml) and acidified to pH 0 with a solution.

  concentrated hydrochloric acid, extracted with dichloromethane (3x100ml).

  After washing with water until neutral and drying, evaporate. The residue obtained is dissolved in dichloromethane and is roughly purified by passage over a short column of silica (5 × 10 cm). The solvents are evaporated and

  recrystallizes from cyclohexane. This gives 1-tertbutoxycarbonyl-

  2- (p-tert-butylphenyl) -6-indolecarboxylate methyl. (1.60g, 61%)

  F: 167 C, Rf = 0.7 (eluent: ethyl ether (50%), hexane (50%)).

- 18 - 2570377

EXAMPLE 10

  2- (p-tert-butylphenyl) -6-indolecarboxylic acid.

  1.25 g (3.1 mmol) of the ester obtained in 9 (d) are stirred for 2 hours with 10Oml of sodium hydroxide in methanol (2N) under reflux. It is evaporated, taken up in water (100 ml), extracted with ethyl ether (3 × 100 ml), the aqueous phase is acidified to pH 4 with a solution of hydrochloric acid N. It is extracted with ether (3 × 100 ml) dry and evaporate the organic phase. The residue obtained is recrystallized from acetonitrile. This gives the acid

  2- (p-tert-butylphenyl) -6-indolecarboxylic acid. (0.75g, 84%).

  F: 297 C, Rf = 0.5 (eluent: mixture of dichloromethane (80%) and methanol

(20%)).

EXAMPLE 11

  1-tert-Butoxycarbonyl-2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-

  naphthyl) -6-indole methyl carboxylate.

  a) 3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthamido) 4-methyl

methyl benzoate.

  In a similar manner to Example 9 (a), we obtain, from 4.95 g

  (30mmol) of methyl 3-amino-4-methylbenzoate and 2- (5,6,7,8-dichloromethane) chloride.

  tetrahydro5,5,8,8-tetramethyl) naphthoyl (7,50g, 30mmol), the 3- (5,6,7,8-tetrahydro)

  methyl trahydro-5,5,8,8-tetramethyl-2-naphthamido) 4-methyl-benzoate.

(9.65g, 93%).

  F: 159 C, Rf = 0.75 (eluent: mixture of dichloromethane (95%) and ethyl ether;

lique (5%)).

  b) 3-N-tert-Butoxycarbonyl- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-

  naphthamido) methyl 4-methyl benzoate.

  In a similar manner to Example 9 (b), we obtain, from 9.85g

  (26 mmol) of the ester obtained in 11 (a), 3-tert-butoxycarbonyl- (5,6,7,8-tert-butoxycarbonyl)

  methyl trahydro-5,5,8,8-tetramethyl-2-naphthamido) -4-methylbenzoate.

(8.50g, 67%)

  F: 132 C, Rf = 0.8 (eluent: ethyl ether).

  c) 4-Bromomethyl-3- [N-tert-butoxycarbonyl- (5,6,7,8-tetrahydro-5,5,8,8-

  methyl tetramethyl-2-naphthamido)] benzoate.

  7.75 g (17.3 mmol) of ester obtained in 11 (b) are treated with 3.08 g of Nbromosuccinimide and 40 mg of benzoyl peroxide in 40 ml of carbon tetrachloride under reflux for 20 hours. It is evaporated to dryness, filtered through a short column of silica (5 × 10 cm), eluting with dichloromethane. The solvents are evaporated and the residue is purified by chromatography ("Waters" Prep 500, silica column, eluent: ethyl ether mixture (5%)).

- 19 -

19 - 2570377

  dichloromethane (15%), and hexane (80%)). This gives a mixture

  containing 20% starting material and 80% 4-bromomethyl-3-

  LN (tert-butoxycarbonyl- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2naphtamido)]

methyl benzoate. (7.2 g).

  d) 7.10 g of the mixture obtained in 11 (c) are dissolved in 40 ml of THF and treated with 3.20 g (12 mmol) of triphenylphosphine. We heat 4 hours

  reflux, cool and add 1.80g (12mmol) of DBU. Stirred 2 hours at 20 ° C.

  After treatment analogous to 9 (d), the

  1-tert-butoxycarbonyl-2- (5,6,7,8, tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)

  6-indole methyl carboxylate. (3.80 g, 56% from the ester obtained in 11 (b)).

  F: 162 ° C, Rf = 0.6 (eluent: dichloromethane).

EXAMPLE 12

  2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) 6-indole acid

  lecarboxylique. In a similar manner to Example 10, starting from 3.40 g (7.3 mmol) of

  the ester obtained in 11 (d), 2- (5,6,7,8-tetrahydro-5,5,8,8-

  tetramethyl-2-naphthyl) -6-indolecarboxylic acid (2.30 g, 90%).

  F: 215 ° C., Rf = 0.6 (eluent: methanol mixture (20%), dichloromethane (80%)).

EXAMPLE 13

  2- (5,6,7,8-Tetrahydro-5,5,8,8-tétramétlhyl-2-naphthyl) -6-indolecarbo-

methyl xylate.

  1.60 g (4.6 mmol) of acid obtained in Example 12 are dissolved in ml of methanol. 0.5ml of concentrated sulfuric acid is added and heated to

  reflux for 8 hours. The methanol is evaporated and the residue is taken up in dichloromethane.

  thane (200ml) and washed with sodium bicarbonate solution. The organic phase is collected, dried and evaporated. The residue is purified by passage to

  through a short column of silica (5x10cm) eluting with dichloromethane

  Thane. There is thus obtained 2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)

  methyl tyl) -6-indolecarboxylate. (1.60g, 96%).

  F: 202 C, Rf = 0.5 (eluent: mixture of ethyl ether (50%) and heptane

(50%)).

EXAMPLE 14

  1-Methyl-2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -6-

methyl indolecarboxylate.

  1.40 g (3.8 mmol) of the ester obtained in Example 13 are dissolved in ml of dry THF and treated with 0.14 g (4.6 mmol) of sodium hydride (80% in

- 20-2570377

  oil). Stir for 1 hour and add 0.65 g (4.4 mmol) of methyl iodide. Stirred for 2 hours, then poured into water (100ml), extracted with dichloromethane (3x100ml). The organic phase is dried and evaporated. The

  The residue obtained is recrystallized from hexane. This gives 1 methyl

  2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -6-indolecarboxylate

methyl. (1.30g, 91%).

  F: 156 C, Rf = 0.65 (eluent: ethyl ether mixture (50%), hexane (50%).

EXAMPLE 15

  1-methyl-2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)

  tyl) -6-indole. 1.00 g (2.65 mmol) of ester obtained in Example 14 are treated in a manner analogous to Example 12. This gives, after recrystallization,

  in a mixture of ethyl acetate and isopropyl ether, the acid

  methyl-2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -6indolecarboxy-

lique (0.90g, 93%).

  F: 256 C, Rf = 0.8 (eluent: ethyl ether).

EXAMPLE 16

  2- (p-tert-Butylphenyl) -5-benzimidazolecarboxylate methyl.

  a) methyl 4-Amino-3- (p-tert-butylbenzamido) benzoate.

  1.65 g (10 mmol) of methyl 3,4-diaminobenzoate and 1.10 g (11 mmol) of triethylamine in 150 ml of ethyl ether are treated dropwise at 0 ° C. with 2.00 g (10 mmol) of sodium chloride. p-tert-butylbenzoyl. Allowed to warm to room temperature and stirred 1 hour. Poured into water (100ml), extracted with dichloromethane (3x100ml), dried and evaporated. We recrystallize in a

  mixture of isopropyl ether and cyclohexane. This gives the 4 amino

  Methyl 3- (p-tert-butylbenzamido) benzoate. (2.40g, 73%)

  F: 175 ° C, Rf = 0.6 (eluent: ethyl ether).

  b) Methyl 2- (p-tert-butylphenyl) -5-benzimidazolecarboxylate.

  2 g of the product obtained in 16 (a) are dissolved in 100 ml of xylene, and 20 mg of p-toluenesulphonic acid (monohydrate) are added. Refluxed for 16 hours, removing the water as it is formed. The solvent is then evaporated, the residue is taken up in dichloromethane (100 ml) and washed with saturated sodium bicarbonate solution. The organic phase is dried, the solvent evaporated and the residue purified by passage over a short column of silica (SxlOcm), eluting with a mixture of dichloromethane (95%) and ethyl ether (5%). The solvents are evaporated and the residue recrystallized in a

  mixture of cyclohexane and isopropyl ether. This gives the 2- (p-

- 21 -

  methyl tert-butylphenyl) -5-benzimidazolecarboxylate. (1.40g, 74%).

  F: 208 C, Rf = 0.6 (eluent: ethyl ether).

EXAMPLE 17

  2- (p-tert-Butylphenyl) -5-benzimidazolecarboxylic acid.

  1.20 g (3.9 mmol) of ester obtained in Example 16 (b) are stirred for 48 hours in 75 ml of a solution of sodium hydroxide in methanol (2N). The methanol is evaporated and 10 ml of water is added. Extracted with ethyl ether and then acidified to pH 4 with a solution of hydrochloric acid (N). Extracted with ethyl ether (3 × 100 ml), dried and evaporated. It is recrystallized from a mixture of ethyl acetate and isopropyl ether. There is thus obtained 2- (p-tert-butylphenyl) -5-benzimidazole carboxylic acid. (0.70 g, 61%). F: 212 C, Rf = 0.6 (eluent: mixture of methanol (20%) and dichloromethane

(80%)).

EXAMPLE 18

  2- (5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -5-benzimidazo-

Methyl carboxylate.

  a) 4-Amino-3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthamido)

methyl benzoate.

  In a manner similar to Example 16 (a), from 2.70 g (16.2 mmol) of methyl 3,4-diaminobenzoate, and from 4.05 g (16.2 mmol) of chloride, , 8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoyl, after recrystallization from a mixture of ethyl acetate and isopropyl ether, the 4-amino-3- (5,6 , 7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphtamido) benzoate

methyl. (5.20g, 84%).

  F: 216 C, Rf = 0.7 (eluent: ethyl ether).

  b) In a similar manner to Example 16 (b), starting at 5.00 g (13 mmol) of

  the ester obtained in Example 18 (a), the 2- (5,6,7,8-tetrahydro-

  Methyl 5,8,8-tetramethyl-2-naphthyl) -5-benzimidazolecarboxylate. (3, 70g,

78%).

  F: 223 C, Rf = 0.75 (eluent: ethyl ether)

EXAMPLE 19

  2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) acid

5-benzimidazolecarboxylique.

  In a manner analogous to Example 17, from 2.90 g (8 mmol) of ester obtained in Example 18 (b), treated with 150 ml of a hydroxide solution

  of sodium in methanol (2N) yields 2- (5,6,7,8-tetrahydro-

- 22 -

  -5,5,8,8-tetramethyl-2-naphthyl) -5-benzimidazolecarboxylic acid (2.40 g, 86%).

  F: 228 ° C., Rf = 0.6 (eluent: dichloromethane (80%), methanol (20%)).

EXAMPLE 20

  2- (5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -6-benzoxazole

methyl carboxylate.

  a) Methyl 3-hydroxy-4-nitro benzoate.

  In a flask, 36.6 g (0.2 mol) of 3-hydroxy-4-

  nitro benzoic acid, 40ml of methanol and 5.4ml of concentrated sulfuric acid. The mixture is refluxed for 8 hours, the reaction medium is evaporated off, the residue is taken up in water, neutralized and extracted with one liter of ethyl ether. The organic phase is decanted, dried over magnesium sulphate and then evaporated. We

  recrystallizes the solid obtained in a hexane / cyclohexane mixture.

(38,5g, 97.7%)

  (F: 89 C, RF = 0.55 (eluent: ethyl ether (50%) / hexane (50%)).

  b) Methyl 4-amino-3-hydroxybenzoate.

  5.9 g (0.03 mol) of methyl 3-hydroxy-4-nitro benzoate, 70 ml of ethyl alcohol and 10.1 g (0.18 mol) of iron are introduced into a flask.

* powder. It is cooled to 10 ° C. and 10 ml of hydrochloric acid are added dropwise.

  concentrated drique then stirred at room temperature for two hours. The reaction medium is filtered and the filtrate is evaporated. The residue is taken up in bicarbonated water / ethyl ether, the organic phase decanted, dried over magnesium sulfate and then evaporated. The solid obtained is recrystallized in a mixture

  cyclohexane / isopropyl ether. (4.5 g, 90%).

  F: 121 C, Rf = 0.55 (eluent: ethyl ether).

  c) In a flask, 3.34 g (0.02 mol) of methyl 4-amino-3-hydroxybenzoate, 4.6 g (0.02 mol) of the acid, 6,7,8-tetrahydro-5, are introduced into a flask. , 5,8,8-tetramethyl-2-naphtho [que, 1.23g (0.02 mol) boric acid and 200ml xylene. Refluxed for 30 hours and separated the water formed with a Dean-Stark. It is evaporated to dryness, taken up in bicarbonate water and extracted with methylene chloride. The organic phase is decanted, dried over magnesium sulphate and then evaporated. The product is purified by flash column chromatography on silica eluting with sodium chloride.

  methylene. It is crystallized from hexane (3.0 g, 41.3%).

  F: 149 C, Rf = 0.3 (eluent: hexane (70%) / ethyl ether (30%)).

EXAMPLE 21

  2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -6-benzoic acid

xazolecarboxylique.

- 23 -

  2.5 g (6.88 mmol) of the ester obtained in (C) are introduced into a flask in 200 ml of methanolic sodium hydroxide (2M); It is heated, reflux 4 hours,

  evaporate to dryness, take up again with water, acidify to p5 = 4 with hydrochloric acid

  Concentrated drique, filters the solid which has precipitated and dries on phosphoric anhydride. The mixture is then recrystallized from an ethyl acetate / tetrahydrofuran mixture (1.5 g, 62.5%).

  F: 310 C, Rf = 0.7 (eluent: ethyl ether).

EXAMPLE 22

  Morpholide of 2- (5,6,7,8, tetrahydro-5,5,8,8-tetramethyl-2-

  naphthyl) -6-benzoxazole carboxylic acid.

  a) 2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-) acid chloride

  naphthyl) -6-benzoxazole carboxylic acid.

  In a flask, 6.98 g (20 mmol) of the acid obtained in Example 21 are introduced into 100 ml of anhydrous dichloromethane. 4 ml (20 mmol) of dicyclohexylamine are added and the mixture is stirred for 2 hours at 20 ° C. The solvents are evaporated and the residue is taken up in anhydrous ether. The salt thus obtained is filtered

(10.5 g) which is used as is.

  The salt is introduced into a flask and 100 ml of dichloride is added.

  dry romethane and 1.45 ml (20 mmol) of thionyl chloride. Shake during

  4 hours at 20 ° C., evaporated to dryness to obtain a white solid (7.25 g, 99%).

  b) Morpholide of 2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-

  naphthyl) -6-benzoxazole carboxylic acid.

  1.05 ml (12 mmol) of morpholine and 50 ml of dichloromethane are introduced into a flask. 1.4 g (4 mmol) of the acid chloride obtained above dissolved in 50 ml of dichloromethane are added dropwise. Stirred for 2 hours at 20 ° C., poured into water, decanted the organic phase,

  Dry on magnesium sulfate, and evaporate the solvents.

  Recrystallized from isopropyl ether and obtained 1.2 g of

  expected compound (72%). F: 149-150C.

EXAMPLE 23

  2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-) ethylamide

  naphthyl) -6-benzoxazole carboxylic acid.

  In a manner analogous to Example 22, starting from 12 mmol of ethyl

  minus 4 mmol of the acid chloride obtained in Example 22 (a),

  2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) ethylamide

  6-benzoxazole carboxylic acid (1.1 g, 74%).

  164-165 ° C (recrystallized from ethyl acetate / isopropyl ether).

pylique). -24-

EXAMPLE 24

  2-hydroxyethyl ester of 2- (5,6,7,8-tetrahydro-5,5,8,8-

  tetramethyl-2-naphthyl) -6-benzoxazole carboxylic acid.

  6.4 ml (114 mmol) of ethylene glycol, 1.9 ml (23 mmol) of pyridine and 50 ml of dichloromethane are introduced into a flask. It is cooled to 0 ° C. and 1.4 g (11 mmol) of the acid chloride obtained in Example 22 (a), dissolved in 50 ml of dichloromethane, are added dropwise. It is then stirred for 2 hours at 20 ° C., poured into water, decanted the organic phase, dried over magnesium sulfate, and the solvents evaporated. The product is rapidly chromatographed on a silica column, using as eluent a mixture

  90% dichloromethane / 10% ether. (4.0 g, 91%).

F: 126-127 ° C

EXAMPLE 25

  Alcohol 2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -6-

benzoxazolyl methyl.

  In a flask, 50 ml of THF and 330 mg of LiAlH 4 are introduced under nitrogen. 2.0 g (5.7 mmol) of the ester obtained are added in small quantities to

  Example 20 (c) and refluxed for 1 hour.

  It is treated with a solution of sodium and potassium double tartrate, filtered, and the organic phase is collected. It is dried over magnesium sulphate and the solvents are evaporated. The residue obtained is purified by chromatography on a silica column using a mixture of dichloromethane (95%) and ether (5%). The product is recrystallized in

cyclohexane. (1 g, 52%).

F: 125-126 C.

EXAMPLE 26

  2- (3- (1-adamantyl) -4-methoxyphenyl] -6-benzimidazole carboxylic acid methyl ester a) 3- (1-adamantyl) -4-methoxybenzoic acid In a flask, 5.4 g (225 g) were added. matome g) magnesium turnings, and 30 ml of THF. A solution of 48.3 g (150 mmol) of 2-adamantyl-4-bromoanisole and 6 ml (70 mmol) of

  1,2-dibromoethane in 300 ml of THF.

  Refluxed for 2 hours, cooled to -70 ° C and passed a stream of CO2 for one hour. The temperature is allowed to rise to 20 ° C., poured into water, acidified to pH 1 with concentrated hydrochloric acid, and extracted with ethyl ether. The organic phase is decanted, dried over

- 25 -

magnesium sulfate and evaporates.

  The solid obtained is recrystallized in ethyl acetate (3.7 g,

86%).

F: 238-239 ° C

  b) 3- (1-adamantyl) -4-methoxybenzoic acid chloride. 200 ml of thionyl chloride are introduced into a flask and 35 g (122 mmol) of the acid obtained above are added in small quantities. Reflux is heated until gas evolution ceases. It is evaporated to dryness, taken up in 100 ml of anhydrous benzene and evaporated to dryness. There is thus obtained 3- (1-adamantyl) -4-methoxybenzoic acid chloride (37 g). F: 153-154 ° C

that we use as is.

  (c) Methyl ester of 4-amino-3- [3- (1-adamantyl) -4-methoxy

xybenzamido] -benzolca.

  3.32 g (20 mmol) of 3,4-diaminobenzoic acid methyl ester, 3.1 ml (22 mmol) of triethylamine and 100 ml of anhydrous ether are introduced into a flask. A solution of the acid chloride obtained above (6.1 g, 20 mmol) in 100 ml of ethyl ether is added dropwise at 0 ° C. The temperature is allowed to rise to 20 ° C. and stirred for 2 hours. The ether phase is decanted into water, decanted, dried over magnesium sulphate and the solvents evaporated. The solid obtained is heated in 100 ml of isopropyl ether at reflux for 15 minutes. It is allowed to return to 20 ° C. and then filtered. 7.4 g of a white solid are thus obtained, which is used as it is for the remainder of the synthesis.

  (d) 2- (3- (-adamantyl) -4-methoxyphenyl) methyl ester

benzimidazole carboxylic acid.

  10.5 g (24 mmol) of the ester obtained are introduced into a flask.

  above, 30 ml of xylene and 4.6 g (24 mmol) of p-tolenesulfonic acid.

  Refluxed for 12 hours, separating the water formed. It is evaporated to dryness and the residue is taken up in sodium bicarbonate solution.

saturated.

  The solid which is purified is filtered by chromatography on a silica column using a mixture of 95% methylene chloride and 5% ether as eluent. The solvents are evaporated and a white solid is obtained which is heated briefly under reflux in 400 ml of ethyl acetate. We let

  cool and thus obtains the expected ester (8.7 g: 87%).

F: 257-8C

EXAMPLE 27

  2- [3- (1-Adamantyl) -4-methoxyphenyl) Methyl Ester

-6-Benzoxazole carboxylic acid.

-26-

  a) Methyl ester of 4-amino-3- [3- (1-adamantyl) -4-methoxy-

benzoyloxy] benzoic acid.

  3.8 g (30 mmol) of 4-amino-3-hydroxybenzoic acid methyl ester, 3.5 ml (25 mmol) of triethylamine and 100 ml of ether are introduced into a flask. The mixture is cooled to 0 ° C. and 7 g (23 mmol) of acid chloride obtained in Example 26 (b) dissolved in 100 ml of ethyl ether are added dropwise. It is then stirred at 20 ° C. for 4 hours, discarded in water, decanted the organic phase, dried over magnesium sulphate and evaporated. The residue obtained is recrystallized from cyclohexane. This gives 8.5 g of

  product that is used as is for the rest of the synthesis.

  b) 2- [3- (1-Adamantyl) -4-methoxyphenyl) Methyl Ester

-6-Benzoxazole carboxylic acid.

  8.5 g (20 mmol) of the ester obtained are introduced into a flask.

  above, 400 ml xylene and 3.7 g (20 mmol) ptoluenesulfonic acid.

  Refluxed for 12 hours, separating the water formed. It is evaporated to dryness, the residue is taken up with saturated sodium bicarbonate solution and the solid obtained is filtered off and purified by chromatography on a column of sodium bicarbonate.

  silica using dichloromethane as eluent.

  Recrystallization from a mixture of ethyl acetate and ether

  isopropyl, 7.7 g (95%) of the desired ester are obtained. F: 183-184C.

EXAMPLE 28 2- [3- (1-adamantyl) -4-methoxyphenyl] -6-benzoxazole carboxylic acid

  lic. 6.4 g (15 mmol) of ester obtained in Example 27 (b) and a solution of sodium hydroxide (16 g) in 300 ml of TRF and 50 ml of water are introduced into a flask. Stirred at room temperature for 72 hours, the solvents evaporated, taken up in water, acidified to pH 5 with hydrochloric acid N. The solid obtained is filtered and washed with water. The solid is extracted with 7 liters of ethyl acetate, dried over magnesium sulphate and then evaporated. The solid is then treated with 500 ml of ethyl acetate, at reflux for 1 hour. Cool and filter the solid (5.9 g, 95%). F: 312314C

EXAMPLE 29

  2- [3- (1-Adamantyl) -4-decyloxyphenyl] -6-benzoxazolecarboxylic Acid Methyl Ester.

  a) 2- (1-adamantyl) -4-bromodecyloxybenzene.

  3.2 g (104 mmol) of sodium hydride are introduced into a flask

- 27 -

  (80% in oil) and 100 ml of N, N-dimethylformamide. A solution of 2-adamantyl-4-bromophenol (29 g, 95 mmol) in 100 ml of N, N-dimethylformamide is added dropwise and stirred until the evolution of gas has ceased. 23 ml (104 mmol) of 1-iododecane are then added and the mixture is stirred for 8 hours at 20 ° C. It is thrown into water, dried over magnesium sulphate and the solvents are evaporated off. The product is purified by chromatography on a silica column,

(eluent: heptane).

  40.7 g (96%) of 2- (1-adamantyl) -4-bromodecyloxy are thus obtained.

benzene. F: 69-70C.

  b) 3- (1-adamantyl) -4-decyloxybenzoic acid.

  In a similar manner to Example 26 (a), starting at 17.9 g

  (40 mmol) of the derivative obtained in Example 29 (a), after crystallization,

  in a mixture of ethyl acetate and isopropyl ether, 3- (1-adamantyl) -4-decyloxybenzoic acid (13.5 g, 82%). F: 151-152 ° C

  c) 3- (1-adamantyl) -4-decyloxybenzoic acid chloride.

  In a manner analogous to Example 26 (b), 7.4 (3- (1-adamantyl) -4-decyloxybenzoic acid, 7.4 g (18 mmol), 7.7 g of

  corresponding acid chloride (100%).

  d) Methyl esters of 4-amino-3- (3- (1-adamantyl) -4-decyl)

  loxybenzoyloxy] benzoic acid and 4-L-3- (1-adamantyl) -4-decyloxybenzamidic acid

  3-hydroxybenzolque. 3.0 g (18 mmol) of 4-amino-3-hydroxybenzoic acid methyl ester, 2.8 ml (20 mmol) of triethylamine and 1 ml of ether are introduced into a flask. It is cooled to 0 ° C. and a solution of the acid chloride obtained above (7.7 g, 18 mmol) in 50 ml of ether is added dropwise. Stirred at 20 ° C. for 2 hours, discarded in water, decanted the organic phase, dried over magnesium sulphate and evaporated. Purification is carried out by chromatography on a silica column, eluting with dichloromethane and thus obtaining successively 2.2 g of 4- [3- (1-adamantyl) -4-decyloxybenzamido] -3-hydroxybenzoic acid methyl ester and then 5 g methyl ester

  4-amino-3- (3- (1-adamantyl) -4-decyloxybenzoyloxy] benzoate;

  e) 2-L3- (1-adamantyl) -4-decyloxyphenyl] -6-benzoxazolecarboxylic acid methyl ester. 6.8 g (12 mmol) of the mixture obtained above, 300 ml of xylene and 2.3 g (12 mmol) of p-toluenesulphonic acid are introduced into a flask. Refluxed for 5 hours by separating the water that forms. It is evaporated to dryness, taken up with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phase is decanted, dried over magnesium sulphate and evaporated. The residue obtained is recrystallized in a

- 28 -

  mixture of ethyl acetate and isopropyl ether. 5.3 g (81%) of 2- [3- (1-adamantyl) -4-decyloxyphenyl) methyl ester are thus obtained.

  -6-Benzoxazole carboxylic acid. F: 127-128C.

EXAMPLE 30

  2- [3- (1-adamantyl) -4-decyloxyphenyl] -6-benzoxazolecarboxylic acid. In a manner analogous to Example 28, starting from 4.6 g (8.5 mmol) of the ester obtained in Example 29 (e), 3.9 g (88%) of acid 2 are obtained. - | 3- (1-adamantyl) -4-decyloxyphenyl] -6-benzoxazolecarboxylic acid:

  F: 200-201 ° C (recrystallized from ethyl acetate).

EXAMPLE 31

  2- [3- (1-Adamantyl) -4-methoxyphenyl) Methyl Ester

-6-benzo (b) furancecarboxylic.

  a) 3- [3- (1-Adamantyl) -4-methoxybenzoyloxy] -4-methylbenzoic acid methyl ester. Analogously to Example 5 (a), from 4.99 g (30 mmol) of 3-hydroxy-4-methylbenzoic acid ester and 9, 14 g (30 mmol) of The acid obtained in Example 26 (b) gives, after chromatography on a silica column (eluent: dichloromethane% / hexane 50% mixture), 12 g of the desired ester (92%). F: 110 C b) 3- [3- (1-Adamantyl) -4-methoxybenzoyloxy] -4-methylomethylbenzoic acid methyl ester. Analogously to Example 5 (b), from 1.70 g (3.9 mmol) of the ester obtained above, 0.70 g of Nbromosuccinimide and mg of benzoyl peroxide in 15 ml. of carbon tetrachloride refluxed under nitrogen for 3 hours, after chromatography on a silica column (eluent: mixture of 30% ethyl ether and 70% hexane), a mixture of the desired product and the starting product which is used as is

for the rest of the synthesis.

  c) Methyl ester of 2- [3- (1-adamantyl) -4-methoxyphenyl) -6-

benzo (b) furancecarboxylic.

  The mixture obtained above is dissolved in 100 ml of dry THF. We

  4.17 g (16 mmol) of triphenylphosphine are added and the mixture is refluxed for 4 hours.

  It is cooled to room temperature and 2.4 ml (16 mmol) of diazabicycloundecene (DBU) are added dropwise. Stirring 30 min at 35 C after the end of the addition, discard in water, acidify to pH 1 (with acid

- 29 -

2570377.

  6N hydrochloric acid) and extracted with ether.

  The organic phase is washed with water, dried over sodium sulfate

magnesium and evaporated.

  The residue is chromatographed on a silica column (eluent: mixture of 20% ethyl ether and 80% hexane). Fluorescent fractions (under UV irradiation at 254 nm) are collected and the solvents evaporated. 1.82 g (27%, yield for steps 31 (b) and 31 (c) combined) of the desired ester are thus obtained. F: 180 C

EXAMPLE 32

  2- [3- (1-adamantyl) -4-methoxyphenyl] -6-benzo (b) furanecarboxylic acid

  xylique. In a manner analogous to Example 8, starting from 1.52 g (3.65 mmol)

  from the ester obtained in Example 31 (c), 2- [3- (1-adamantyl) -

  4-methoxyphenyl] -6-benzo (b) furancecarboxylic acid (1.32 g, 90%). F: 290 C

EXAMPLE 33

  2- [3- (1-Adamantyl) -4-methoxyphenyl] -6benzo (b) thiophenecarboxylic acid methyl ester. a) 4-t 3- (1adamantyl) -4-methoxybenzoylthio] -4-methylbenzoic acid methyl ester. Analogously to Example 1 (a), starting from 5.47 g (30 mmol) of methyl 3-mercapto-4-methylbenzoate, 4.6 ml (33 mml) of triethylamine, and 9.14 g (30 mmol) of the acid chloride obtained

  Example 26 (b) gives the methyl ester of 4- [3- (1) -ammonium

  tyl) -4-methoxybenzoylthio] -4-methylbenzoate (12.83 g, 95%). F: 140 ° C (b) 4- [3- (1-Adamantyl) -4-methoxybenzoylthio] -4-bromomethylbenzoic acid methyl ester. In a manner similar to Example 1 (b), starting from 12.50 g (28 mmol) of the ester obtained above, 4.94 g (28 mmol) of N-bromosuccinimide and 100 mg of benzoyl peroxide, in 200 ml of carbon tetrachloride, after chromatography on a silica column (eluent: 40% ethyl ether / 60% hexane), a mixture containing the starting material and the desired product which is used is obtained what

for the rest of the synthesis.

  c) 2- [3- (1-Adamantyl) -4-methoxyphenyl] -6benzo (b) thiophenecarboxylic acid methyl ester. In a similar manner to Example I (c), from the totality of the mixture obtained above, 4.55 g (17.5 mmol) of triphenylphosphine, and of

- 30 -

  2.60 ml (17.5 mmol) of DBU, after chromatography on a silica column (eluent: 40% dichloromethane / hexane 60% mixture), the desired ester is obtained

  (1.68 g, 14% - yield for steps 33 (b) and 33 (c) combined).

F: 172 C

EXAMPLE 34

  2- [3- (1-adamantyl) -4-methoxyphenyl] -6-benzo (b) thiophene-

  carboxylic acid. In a manner analogous to Example 2, starting from 1.32 g of ester obtained

  in Example 33 (c), 1.15 g (90%) of the corresponding acid is obtained.

F: 305 C

EXAMPLE 35

  Methyl ester of 2- (3-tert-butyl-4-methoxyphenyl) -6-ben-

zo (b) furancarboxylic acid.

  a) 3-tert-butyl-4-methoxybenzoic acid.

  In a manner similar to Example 26 (a), from 12.16 g (50 mmol) of 4-bromo-3-tert-butyl-methoxybenzene, 1.34 g (55 mg of g) of magnesium, an excess of carbon dioxide, 8.31 g (80%) of

  3-tert-butyl-4-methoxybenzoic mp 190 C.

  b) 3-tert-Butyl-4-methoxybenzoic acid chloride.

  Analogously to Example 22 (a), starting from 19.0 g (92 mmol) of acid obtained above, 18.3 ml (92 mmol) of dicyclohexylamine, the salt obtained etan.t treated 6.7 ml (92 mmol) of thionyl chloride give 19.8 g (95%) of acid chloride (oil

  pale yellow), which is used as for the rest of the synthesis.

  c) Methyl ester of 3- [3-tert-butyl-4-methoxybenzoyloxy -4-methylbenzoic acid. Analogously to Example 5 (a), from 14.5 g (87 mmol) of methyl 3-hydroxy-4-methylbenzoate and 19.8 g (87 mmol) of the acid chloride obtained therein. above, after chromatography on a silica column (eluent: 60% dichloromethane / 40% hexane mixture), 3-3-tert-butyl-4-methoxybenzoyloxy] -4-methylbenzoic acid methyl ester (27.7 g) is obtained; , 94%). F: 152C

  d) Methyl ester of 4-bromomethyl-3- (3-tert-butyl-4-methoxy)

xybenzoyloxy) -benzoic acid.

  Analogously to Example 31 (b), from 27.3 g (76.5 mmol) of the above ester, and 13.6 g (76.5 mmol) of N-bromosuccinimide, using 100 mg of benzoyl peroxide as

- 31 -

  After chromatography on a silica column (eluent: 60% dichloromethane / 40% hexane mixture), a mixture of the starting material and of the monobromous product containing traces of the dibromo product is obtained.

  used as is for the rest of the synthesis.

  e) Methyl ester of 2- (3-tert-butyl-4-methoxyphenyl) -6-ben-

zo (b) furanecarboxylic.

  The mixture obtained above (27.6 g) is dissolved in 100 ml of dry THF. 16.6 g (63 mmol) of triphenylphosphine are added and the mixture is heated to reflux.

for 4 hours.

  It is cooled to 20 ° C. and 9.5 ml (63 mmol) of DBU are added dropwise under nitrogen. After the addition is complete, the mixture is stirred for a further 20 minutes at 80 ° C. It is thrown into water and acidified to pH 1 (with 6N hydrochloric acid) and extracted.

  three times with 200 ml of dichloromethane.

  The organic phase is washed with a saturated solution of sodium chloride, dried over magnesium sulphate, the solvents are evaporated and the residue is purified by silica column chromatography (eluent: mixture

40% dichloromethane / 60% hexane).

  The fluorescent fractions are collected (under UV irradiation at 254 nm) and the solvents are evaporated to give 2 (3-tert-butyl-4-methoxyphenyl) -6-benzo (b) furanecarboxylic acid methyl ester (11). , 2 g,

43%). F: 179 C

EXAMPLE 36

  2- (3-tert-butyl-4-methoxyphenyl) -6-benzo (b) furanecarboxylic acid

lic.

  In a similar manner to Example 8, from 7.64 g (22.5 mmol) of the ester obtained in Example 35 (e) treated with a mixture of methanol (500 ml) and aqueous sodium hydroxide ( 135 ml, 5N), 2- (3-tert-butyl-4-methoxyphenyl) -6-benzo (b) furancarboxylic acid (6.74 g,

92%). F: 235 C.

EXAMPLE 37

  2- (3- (1,1-Dimethyldecyl) -4-methoxy-methyl ester

  phenyl] -6-benzo (b) furancecarboxylic acid.

  a) 4-bromo-2- (1,1-dimethyldecyl) phenol.

  A mixture of 2-methyl-1-undecene (35.6 g, 211 mmol), parabromophenol (36.6 g, 211 mmol) and Dowex 50x12 resin (100-200 mesh) previously washed with water, rinsed with acetone and dried in an oven for 3 hours at C, is heated at 100-110 C for 48 hours. Cool to temperature

- 32 -

  ambient and silica column chromatography (eluent: dichloromethane

  40% methane / 60% hexane), thus obtaining 4-bromo-2- (1,1-dimethyldecyl) -

  phenol as a pale yellow oil (30.85 g, 43%).

  The product is used as is for the rest of the synthesis.

  b) 4-bromo-2- (1,1-dimethyldecyl) anisole The compound obtained above (30.85 g, 90 mmol) is solubilized in ml of dry THF and then treated with 2.7 g (90 mmol) sodium hydride (80% in oil), which is added in small portions. After the addition was complete, the mixture was stirred for 30 minutes at room temperature and 12.8 g (90 mmol) of methyl iodide were then added. The mixture is stirred for 2 hours at 20 ° C., the solvent is evaporated off, and the residue is purified by chromatography on a silica column (eluent: dichloromethane mixture).

% / hexane 60%).

  After evaporation of the solvents, the desired product is obtained under the

  form of a yellow oil (29.3 g, 91%).

  c) 3- (1,1-Dimethyldecyl) -4-methoxybenzoic acid.

  The brominated derivative obtained above (28.46 g, 80 mmol) dissolved in mL of dry THF is added slowly to turn magnesium (2.34 g, 96 mAtg) and an iodine crystal. At the beginning of the addition it is heated until the reaction is initiated (establishing a reflux). This reflux is

  then maintained by the rate of addition of the brominated derivative.

  The addition is complete, the stirring is continued for 30 minutes at 50 ° C., cooled

  at 0 ° C and passed a stream of carbon dioxide for 3 hours.

  The THF is then evaporated, 300 ml of water are added and acidified to pH 1 (using 6N hydrochloric acid). Extracted with 3x300 ml of ethyl ether. The organic phase is washed with a saturated solution of NaCl,

  dried over magnesium sulfate, and the solvents evaporated.

  The solid obtained is washed with 50 ml of cold hexane and dried at

the oven at 800C.

  15.25 g of 3- (1,1-dimethyldecyl) -4-methoxybenzoic acid are obtained

(59%). F: 112 C

  d) 3- (1,1-Dimethyldecyl) -4-methoxybenzoic acid chloride.

  In a manner similar to Example 22 (a), from 14.4 g (44.8 mmol) of acid obtained above, 9 ml (44.8 mmol) of dicyclohexylamine, the salt obtained being treated 3.26 ml (44.8 mol) of thionyl chloride for 16 hours at 20 ° C., the acid chloride is obtained.

  raw used as is for the next step.

  e) Methyl ester of 3-L3- (1,1-dimethyldecyl) -4-methoxy-

benzoyloxy] -4-methylbenzoic acid.

  Analogously to Example 35 (c), from 6.98 g (42 mmol) of methyl 3-hydroxy-4-methylbenzoate, all of the

- 33- 2570377

  crude acid chloride obtained in Example 27 (d), and 4.25 g (42 mmol) of

  triethylamine, the methyl ester of 3-E 3- (1,1-dimethyl)

  decyl) -4-methoxybenzoyloxy-4-methylbenzoic (17.84 g, 91% yield for steps 37 (d) and 37 (e) combined); in the form of a yellow oil that crystallizes. F: 90 C

  f) Methyl ester of 4-bromomethyl- [3- (1,1-dimethyldecyl) -4-

methoxybenzoyloxyjbenzoic acid.

  Analogous to Example (d), starting from 17.4 g (37 mmol) of the ester obtained above, and 6.6 g (37 mmol) of N-bromosuccinimide, one obtains after purification by column chromatography (eluent: mixture of 40% ethyl ether / 60% hexane), a mixture containing the desired monobromate product, the starting material, and traces of

  derivative dibromed. This mixture is used as it is for the next step.

  (g) Methyl ester of 2- E 3- (1,1-dimethyldecyl) -4-methoxy-

  phenyl-6-benzo (b) furancecarboxylic acid.

  Analogous to Example 35 (e), from the totality of the mixture obtained above, 9.73 g (37 mmol) of triphenylphosphine and 5 ml (37 mmol) of DBU were obtained after three recrystallizations in

  hexane, 3.02 g of 2-3- (1,1-dimethyldecyl) methyl ester

  methoxyphenyl-6-benzo (b) furanecarboxylic 18% yield for all of steps 37 (f) and 37 (g) F: 95 C

EXAMPLE 38

  2- [3- (1,1-Dimethyldecyl) -4-methoxyphenyl] -6-benzo (b) furan

necarboxylique.

  In a similar manner to Example 36, from 1.85 g (4 mmol)

  of ester obtained in Example 37 (g), 2- [3- (1,1-dimethyl)

  decyl) -4-methoxyphenyl-6-benzo (b) furancarboxylic acid (1.47 g, 82%).

F: 150 C

EXAMPLE 39

  2- [3- (1-adamantyl) -4-methoxyphenyl] -5-benzimidazole carboxylic acid. 7.8 g (19 mmol) of the ester obtained in Example 26 (d) and 300 ml of 2N methanolic sodium hydroxide are introduced into a flask. Refluxed for 24 hours, evaporated to dryness, taken up in water, acidified to pH5 with hydrochloric acid, filtered the solid, and washed with water. The solid is then dried under vacuum in the presence of P2O5. The solid is extracted with THF (1 liter), then the THF is evaporated after filtration of the insoluble material. The product

- 34 -

  is heated under reflux for 1 hour in a mixture of THF (300 ml) and ethyl acetate (300 ml). After cooling, the solid is filtered and

  7 g (93%) of 2- [3- (1-adamantyl) -4-methoxyphenyl) -5 benzene are obtained.

* Midazolecarboxylique. F: 358-359C.

EXEPLE 40

  2- [3- (1-Adamantyl-4-hydroxyphenyl) Methyl Ester

-5-benzimidazole carboxylic acid.

  a) 2- (1-adamantyl) -4-bromo-tert-butyldimethyl siloxybenzene.

  30.7 g (100 mmol) of 2- (1-adamantyl) are introduced into a flask.

  4-bromophenol, 15.4 ml (110 mmol) of triethylamine, 500 mg (4 moles) of

  4- (N, N-dimethylamino) pyridine and 200 ml of T.H.F.

  Under nitrogen, a solution of 15.7 g (104 mmol) of tert-butyldimethylsilyl chloride in 100 ml of DMF was added dropwise. stirred 4 hours, thrown in water, extracted with ether and decanted phase

  organic. After washing with water, drying over magnesium sulphate and evapo-

  solvent, the residue obtained is purified by passage over a column of

silica eluting with hexane.

  3.62 g of the expected product are thus obtained. F: 111-112C.

  b) 3- (1-adamantyl) -4-tert-butyldimethylsilyloxybenzoic acid.

  1.18 g (48.8 mg) of magnesium and ml of T.H. F. are added to a flask. 13.7 g (32.5 mmol) of the product are added dropwise.

  obtained above in 100 ml of T.H.F. and refluxed for 2 hours.

  It is cooled to -78 ° C. and a stream of carbon dioxide is passed into the reaction medium. Allowed to warm to room temperature, discarded in water and acidified to pH 1 with 5 N hydrochloric acid. After extraction with ether and conventional treatment, the solid obtained is heated in 200 ml.

of isopropyl ether at reflux.

  After cooling, the solid is filtered and thus obtained

  8.2 g (65%) of 3- (1-adamantyl) -4-tert-butyldimethylsilyloxy benzoic acid.

F: 245-246C.

  c) 3- (1-Adamantyl) -4-tert-butyldimethylsilyloxybenzoic acid chloride. 6.45 g (16.7 mmol) of the acid obtained above, 3.3 ml (16.7 mmol) of dicyclohexylamine and 100 ml of methylene chloride are introduced into a flask. Stirred at room temperature for 2 hours, then 1.35 ml (18.4 mmol) of thionyl chloride and stirred for 2 hours. Evaporated to dryness, taken up in 200 ml of ether, filtered dicyclohexylammonium chloride and evaporated the solvents. 6.9 g of a solid which is used as

- 35 -2570377

- - 35 -

what for the next step.

  d) Methyl ester of 4-amino-3- [3- (1-adamantyl) -4-tert-

  butyl dimethylsilyloxy benzamidoj-benzoic acid.

  2.77 g (16.7 mmol) of 3,4-diaminotin are introduced into a flask.

  methyl benzoate, 2.6 ml (18.4 mmol) of triethylamine and 100 ml of ether. A solution of 6.75 g (16.7 mmol) of the acid chloride obtained above in 100 ml of ether is added dropwise and the mixture is stirred for 2 hours at 20 ° C.

  Pour into the water, extracted with methylene chloride, decanting the organic phase

  It is dried over magnesium sulfate and the solvents are evaporated. The residue obtained is purified by passage through a silica column, eluting with a mixture of 95% dichloromethane and 5% ether. This gives 6.9 g (78% of the ester).

expected. F: 216-217 C.

  e) 2- (3- (1-adamantyl) -4-tert-butyldimethyl) methyl ester

  thylsilyloxy phenyl] -5-benzimidazole carboxylic acid.

  6.3 g (11.6 mmol) of the product obtained above, 2.2 g (11.6 mmol) of p-toluenesulphonic acid and 100 ml of xylene are introduced into a flask. Refluxed for 2 hours, evaporated to dryness, taken up with saturated sodium bicarbonate solution, extracted with methylene chloride, decanted the organic phase, dried over magnesium sulfate and evaporated. The residue is purified by passage through a silica column (eluent = mixture of 95% dichloromethane and 5% ether). 5.5 g (92%) of the ester are thus obtained.

expected. F: 277-278C.

  f) 2- [3- (1-adamantyl) -4-hydroxyphenyl acid methyl ester

-5-benzimidazole carboxylic acid.

  5.2 g (10 mmol) of the ester obtained above and 100 ml of T.H.F. are introduced into a flask. 1 ml (11 mmol) of a solution of tetrabutylammonium fluoride in T.H.F. are added dropwise. (M) and stir 2 hours. It is thrown into water, the solid filtered, washed with water and extracted with T.H.F. T.H.F. is evaporated and collected a white solid which is heated in a mixture of 600 ml of ethyl acetate and 100 ml of T.H.F. Allowed to warm to room temperature then filter the solid obtained (3.8 g

%). F - 328-330 C.

EXAMPLE 41

  Methyl ester of 2- (5,6,7,8-tetrahydro-5,5,8,8-tetrahydro

  methyl-2-naphthyl) -6-benzothiazole carboxylic acid.

  a) Methyl ester of 4-amino-3- (5,6,7,8-tetrahydro-5,5,8,8-tetrahydro)

  2-methanylbenzoylthio benzoic acid.

  5.4 g (14.8 mmol) of 4,4'-diamine are introduced into a flask.

- 36 -

  methyl-3,3'-dithiodibenzoate, 3.9 g (14.8 mmol) of triphenylphosphonate

  phine, 75 ml of dioxane and 5 ml of water. It is refluxed under nitrogen for 4 hours. It is cooled to 20 ° C. and 6.2 ml (44.5 mmol) are added dropwise.

  of triethylamine followed by 7.4 g (29.6 mmol) of

  Trahydro-5,5,8,8-tetramethyl-2-naphthol dissolved in 50 ml of ether. It is stirred for 1 hour at 20 ° C., the mixture is poured into water and extracted with ether, the organic phase is decanted, dried over magnesium sulphate and evaporated. Recrystallized from a mixture of isopropyl ether 66% - ethyl acetate 33 X and obtained

  8 g of the expected ester (68%). F: 154-155C.

  b) Methyl ester of 2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl)

  thyl-2-naphthyl) -6-benzothiazole carboxylic acid.

  9 g (22.6 mmol) of the ester obtained above, 4.3 g (22.6 mmol) of p-toluenesulphonic acid and 200 ml of xylene are introduced into a flask. Refluxed for 2 hours, evaporated to dryness, taken up with

  dichloromethane and washed with saturated sodium bicarbonate solution.

  After usual treatment, a residue is obtained which is recrystallized from isopropyl ether. 8.2 g (95%) are thus obtained of the methyl ester of

  2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -6-benzothiazole acid;

carboxylic acid. F: 143-144 ° C

EXAMPLE 42

  2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -6-benzoic acid

  thiazolecarboxylic. 5.6 g (14.7 mmol) of the ester obtained in Example 41 (b), 200 ml of a 2N sodium hydroxide solution in methanol and ml of T.H.F. are introduced into a flask. It is stirred for 4 hours at 20 ° C., evaporated to dryness, taken up in water and acidified to pH 5 with N hydrochloric acid, the solid obtained filtered and washed with water until neutral. The solid is extracted with ether, dried over magnesium sulphate, evaporated and recrystallized from ethyl acetate. We

  thus obtaining 4 g (75%) of 2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl)

  2-naphthyl) -6-benzothiazolecarboxylique. Mp = 292-293C.

EXAMPLE 43

  2- (4,4-Dimethyl-2,3-dihydro-1-benzo) acid methyl ester

  pyran-6-yl) -5-benzimidazolecarboxylique.

  a) 4,4-Dimethyl-2,3-dihydro-1-benzopyran-6-carboxylic acid.

  To a solution of sodium hydroxide (21 g) in 110 ml of water cooled to -5 ° C., 9 ml of bromine are added dropwise. After 15 minutes, 6 g of

- 37 -

  6-acetyl-4,4-dimethyl-2,3-dihydro-1-benzopyran in dioxane (50 ml).

  Allowed to rise to 20 C and then heated to 50 C, cooled and added 70 ml of a solution of 9.2 g of sodium metabisulfite and 42 ml of concentrated hydrochloric acid. Dilute with water, filter, wash the precipitate to neutrality. After crystallization in a mixture

  acetone-water, the expected acid is obtained with 90% yield.

  (b) 4,4-dimethyl-2α-dihydro-1-benzopyran-6-carbohydrate chloride

  xylique. In a flask, 90 mg (0.43 mmol) of the acid obtained at

  Example 42 (a) is suspended in 0.8 ml dry dichloromethane.

  87 μl (0.43 mmol) of dicyclohexylamine are added dropwise and the reaction medium becomes clear. Stirred 30 min at room temperature

  and added 32 μl (0.43 mmol) of thionyl chloride.

  After stirring overnight at ambient temperature, the dicyclohexylamine hydrochloride is filtered, the dichloromethane is evaporated and the residue is used.

  produced as is for the next step.

  (c) Methyl ester of 4-amino-3- (4,4-dimethyl-2,3-dihydro-1-ben-

  zopyran-6-carboxamido) -benzo; that. The crude product obtained above is dissolved in 2 ml of ethyl ether and a mixture of 72.5 mg (0.43 mmol) of 3,4-diamino benzoic acid methyl ester is added dropwise, 61 μl (0.43 mmol) of

triethylamine and 2 ml of ether.

  Stirred 2 hours at room temperature and then thrown into water (20 ml). Extracted with 3 fractions of 10 ml of ethyl ether and the organic phase is then washed with a saturated solution of sodium hydride, dried over

  magnesium sulfate, filtered and evaporated. The residue obtained is chromatographed

  on a silica column (eluent - 80% ether mixture - 20% hexane). We

  thus obtaining 82 mg (53%) of the expected product. F: 213 C.

  d) Methyl ester of 2- (4,4-dimethyl-2,3-dihydro-1-benzo)

  pyran-6-yl) -5-benzimidazole carboxylic acid.

  In a flask, the ester obtained above (82 mg, 0.23 mmol), 44 mg (0.23 mmol) of p-toluenesulphonic acid monohydrate and ml of xylene are placed. The mixture is refluxed for 1 hour, cooled to C and chromatographed on a silica column (eluent = 80% ether - hexane

20%).

  There is thus obtained 20 mg (26%) of 2- (4,4-dimethyl-2,3-dihydro-1-benzopyran-6-yl) -5-benzimidazolecarboxylic acid methyl ester.

F: 110.115 ° C

- 38 -

EXAMPLES OF COMPOSITIONS

A - ORAL ROUTE

  Example 1: Tablet of 0.2 g Composed of Example 4 ........ 0.001 g Starch ..

  .................... 0.114g Dicalcium phosphate ........ 0.020g Silica .... DTD: ......... .. 0, 020g Lactose ............... 0.030gTalc ..................... DTD: .... 0.010 g Magnesium stearate 0.05 g In this example, the compound of Example 4 can be replaced by the same. DTD: amount of the compound of Example 34.

  Example 2: Tablet of 0.5 g, formula of the powder Compound of Example 1

  .... O, OOlg Starch of mals ................ 0,150g Magnesium stearate ... DTD: ...... 0,250g Sucrose qsp .... ............ 0.500g The powder is packaged in a capsule made of gelatin and titanium dioxide. In this example, the compound of Example 1 can be replaced by DTD: the same amount of the compound of Example 35.

  EXAMPLE 3 0.4g Capsule Containing a Suspension Compound of Example 8 0.005g Glycerin ..................... 0.200g Sucrose ........

  .......... 0.050g Polyethylene glycol 400 ....... O, 050g Purified water qs ............... 0.400g This suspension is packed in a capsule composed of gelatin, .. DTD: glycerine, titanium dioxide and water.

  In this example, the compound of Example 8 can be replaced by the same

  amount of the compound of Example 31.

  Example 4: Oral suspension in 5ml ampoules Composed of Example 19 .....

  . 0,001g Glycerine ..................... 0,500g Sorbitol 70% ............. DTD: ... 0,500g Sodium saccharin ....... 0.010g Methyl parahydroxybenzoate 0.040g Ar8me ......................... qs Purified water qs ... In this example, the compound of Example 19 can be replaced by the same. DTD: amount of the compound of Example 39.

- 39 -

B - TOPICAL ROUTE

  Example 5: Ointment compound of Example 4 ........ 0.1OOlg Stearyl alcohol ............ 3,000g Lanolin ............ .......... 5,000g Vaseline ...................... 15,000g Distilled water qsp .......... ... 100, 000g Example 6: Oil cream in nonionic water Composed of Example 2 ...

  ... 0.050g Cetyl alcohol .............. 3,000g Stearyl alcohol ....... DTD: ..... 3,400g Cetyl oxyethylenated alcohol (20 moles) .. ....... 0,630g Oxyethylenated stearyl alcohol (20 moles) ........ 1,470g Glycerol monostearate ...... 2,000g Vaseline oil .......... .... 15,000g Glycerin ..... DTD: ............... 10,000g Preservatives ................. qs Distilled water qs ............ 100,000g In this example, the compound of Example 2 can be replaced by the same..DTD: amount of the compound of Example 34.

  EXAMPLE 7 Ointment Compound of Example 1 ........ 0.020 g Isopropyl Myristate ........ 81.700 g Fluid Vaseline Oil ...... 9.100 g Silica sold by the Company Degussa company under the name "Aerosil 200" ................. In this example, the compound of Example 1 can be replaced by the same

  amount of the compound of Example 35.

  EXAMPLE 8 Cream Oil in Anionic Water Compound of Example 14 ....... 0.010g Sodium Dodecyl Sulfate ...... 0.800g Glycerol ............. .......

  . 2,000g Stearyl alcohol ............. 20,000g Triglycerides of capric / caprylic acids sold by Dynamit Nobel under the name of..DTD: - 40 -

  "Miglyol 812" .................. 20,000g Preservatives ................. qs Demineralized water ..... ........ 100 OOOg

Example 9: Gel

  Compound of Example 19 ....... 0.005g Hydroxypropyl cellulose sold by the company Hercules under the name "Klucel HF" ............ 2,000g Water / ethanol (50: 50) QSP ....... 100,000g 1 In this example, the compound of Example 19 can be replaced by the same

  amount of the compound of Example 39.

  Example 10: Eye Drops Composed of Example 19 * .... 0.005 g Na 2 HPO 4 0.1 M ....

  ......... 80,000m NaH2 PO4 O, 1M ............... 20,000ml * 100% of the particles of this compound must be less than. .DTD: microns.

  This eye drops is a suspension of pH = 7.4 (pH of the lacrimal fluid) and isotope

in relation to tears.

  After conditioning in a suitable ampoule, the product is sterilized.

  The product should be vigorously stirred before use.

- 41 -

Claims (17)

  1. Heterocyclic aromatic compounds characterized in that they have the following general formula: y Ar \ / dXIII R. (I) R2   in which: R 1 represents: (i) -CH 3 (ii) -CH 2 OH (iii) -C, -R 3 O R 3 represents a hydrogen atom, the radical -OR 4, R 4 representing a hydrogen atom, an alkyl radical having from 1 to 20 carbon atoms, a mono- or polyhydroxyalkyl radical or R represents the radical -N r '3' 1>% r "r 'and r" representing a hydrogen atom, a lower alkyl radical or taken together form a heterocycle, R2 represents a hydrogen atom or the radical -CH3, Ar represents an aromatic radical corresponding to one of the following formulas: CH CH (a) (AT) CH CH (b) (B) Z being O or S - 42 -   (c) (C) R 5 R 5 representing a lower alkyl radical and (d) (D) R6   R 7 R 6 representing a hydrogen atom or an alkyl radical having 1 to 10 carbon atoms and R 7 representing a branched alkyl radical having 4   to 12 carbon atoms or a cycloalkyl radical.   Y represents CH or a nitrogen atom, and X represents an oxygen atom, a sulfur atom or the -N-R8 radical, R8 representing a hydrogen atom, a lower alkyl radical or a lower alkoxycarbonyl radical, under reserves on the one hand that when Y represents CH and X represents an oxygen or sulfur atom, Ar is different from a radical of formula (C) in which R5 = -CH3 and on the other hand that when Y represents a nitrogen atom and X represents an oxygen atom, Ar is different from a radical of formula (C) or of formula (D) in which R 6 represents an alkyl radical having 1 to 4 carbon atoms and R 7 represents a branched alkyl radical having from 4 to 12 carbon atoms.   2. Compounds according to claim 1 characterized in that the lower alkyl radical is a radical having 1 to 6 carbon atoms and is taken from the group consisting of a methyl, ethyl, isopropyl, butyl and tert-butyl.   3. Compounds according to claim 1, characterized in that the lower mono-hydroxyalkyl radical is a radical having 2 or 3 carbon atoms and is taken from the group consisting of 2 hydroxyethyl and 2-hydroxypropyl radicals and that the polyhydroxyalkyl radical is a derived radical   glycerol, pentaerythritol, or mannitol.   4. Compounds according to claim 1 characterized in that the lower alkoxycarbonyl radical is a methoxycarbonyl radical, ethoxy   carbonyl, isopropoxycarbonyl or tert-butoxycarbonyl. - 43 -   5. Compounds according to claim 1, characterized in that the radicals r 'and r ", taken together, form a heterocycle taken from the group consisting of a piperidino, piperazino, morpholino or pyrrolidino radical. 6. Compounds according to claim 1 characterized in that the cycloalkyl radical is a cyclohexyl, methylcyclohexyl or adamantyl radical.   Compounds according to any one of claims 1 to 6   characterized by the fact that they correspond to the following formula: CH3 CH3y CH   in which: R represents -CH O20H or -C-R 2 0   R representing -0 R or -N R 3 4 R "R 4 representing a hydrogen atom, a radical -CH 3 or -CH 2 CH 2 OH r 'and r" identical or different representing a hydrogen atom, a lower alkyl radical or taken together form a morpholino ring Y represents CH or a nitrogen atom and X represents a sulfur atom, an oxygen atom or N-R8, R8   being a hydrogen atom, the radical -CH3 or -CO2 tert-butyl.   8. Compounds according to any one of claims 1 to 6   characterized by the fact that they correspond to the following formula: CH X OR   In which: R4 represents a hydrogen atom or a radical -CH3 - 44 -   Y represents CH or a nitrogen atom and X represents a sulfur atom, an oxygen atom or N-R8, R8   being a hydrogen atom or the radical -CO 2 tert-butyl.   9. Compounds according to any one of claims 1 to 6   characterized by the fact that they correspond to the following formula: Y X 0-R (IV)   R60 R? in which: R4 represents a hydrogen atom or a radical CH3 R6 represents the radical -CH3 or C10H21 R7 represents the radical tertbutyl, dimethyl-l, 1 decyl or adamantyl Y represents CH or a nitrogen atom and X represents an atom of sulfur, an oxygen atom or N-R8, R8 being a hydrogen atom.   10. Compounds according to any one of the preceding claims   characterized by being in the group consisting of: methyl 2- (p-tert-butylphenyl) -6-benzo (b) thiophenecarboxylate, 2- (p-tert-butylphenyl) -6-acid -benzo (b) thiophene,   2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -6-benzo (b) thiophene- methyl carboxylate,   2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -6-benzo (b) -   thiophenecarboxylic acid, - methyl 2- (p-tert-butylphenyl) benzo (b) furancecarboxylate, 2- (p-tert-butylphenyl) -benzo (b) furancarboxylic acid,   2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -6-benzo (b) - methyl furanecarboxylate,   2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -6-benzo (b) -   furanecarboxylic acid, 1-tert-butoxycarbonyl-2- (p-tert-butylphenyl) -6-indolecarboxylate, 2- (p-tert-butylphenyl) -6-indole carboxylic acid,   1-tert-butoxycarbonyl-2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-   methyl naphthyl) -6-indole carboxylate, - 45 -   methyl 2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -6indolecarboxylate, 2- (5,6,7,8-tetrahydro) -5,5,8,8-tetramethyl-2-naphthyl) -6-indole carboxylic acid, - 1-methyl-2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) Methyl 6-indole carboxylate,   1-methyl-2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -6-   indolecarboxylic acid, methyl 2- (p-tert-butylphenyl) -5-benzimidazole carboxylate, 2- (p-tert-butylphenyl) -5-benzimidazole carboxylic acid,   2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -benzimidazole methyl carboxylate,   2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) benzimidazole acid; carboxylic acid,   2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -6-benzoxazole methyl carboxylate,   2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -6-benzoxazole acid; carboxylic acid,   the morpholide of 2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) tyl) -6-benzoxazole carboxylic acid,   2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) ethylamide tyl) -6-benzoxazole carboxylic acid,   2-hydroxyethyl ester of 2- (5,6,7,8-tetrahydro-5,5,8,8tetrahydrate)   methyl-2-naphthyl) -6-benzoxazole carboxylic acid, 2- (5,6,7,8-tetrahydro-5-5,8,8-tetramethyl-2-naphthyl) -6-benzoxazolyl methyl alcohol,   2-L3- (1-adamantyl) -4-methoxyphenyl-5-benzyl methyl ester carboxylic midazol,   2- [3- (1-adamantyl) -4-methoxyphenyl] -6-benzoic acid methyl ester   xazole carboxylic acid, 2- [3- (1-adamantyl) -4-methoxyphenyl] -6-benzoxazole carboxylic acid,   the methyl ester of 2- [3- (1-adamantyl) -4-decyloxyphenyl] -6-   zoxazole carboxylic acid, 2 [3- (1-adamantyl) -4-decyloxyphenyl] -6-benzoxazole carboxylic acid,   2- (3- (1-adamantyl) -4-methoxyphenyl] -6-benzoic acid methyl ester (b) carboxylic furan,   2- (3- (1-adamantyl) -4-methoxyphenyl] -6-benzo (b) furan carboxy- lic,   2- [3- (1-adamantyl) -4-methoxyphenyl] -6-benzoic acid methyl ester (b) thiophene carboxylic acid, -46 - 2570377   2- [3- (1-adamantyl) -4-methoxyphenyl] -6-benzo (b) thiophene carboxylic acid lic,   2- (3-tert-butyl-4-methoxyphenyl) -6benzo (b) - methyl ester   carboxylic furan, - 2- (3-tert-butyl-4-methoxyphenyl) -6benzo (b) furan carboxylic acid, - 2- [3- (1,1-dimethyl-decyl) - methyl ester methoxyphenyl] -6-benzo (b) furan carboxylic acid, -   2- (3- (1,1-dimethyldecyl) -4-methoxyphenyl] -6-benzo (b) furanecarboxylic acid,   2- [3- (1-adamantyl) -4-methoxyphenyl] -5-benzimidazole carboxylic acid.   2- [3- (1-adamantyl-4-hydroxyphenyl) -5benzic acid methyl ester carboxylic midazole,   2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl) methyl ester   2-naphthyl) -6-benzothiazole carboxylic acid,   2- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) -6-benzothiazole zolecarboxylique,   and the methyl ester of 2- (4,4-dimethyl-2,3-dihydro-1-benzopyran) 6-yl) -5-benzimidazole carboxylic acid.   11. Drug characterized by the fact that it is a compound of   formula (I) according to any one of claims 1 to 10.   12. The medicament as claimed in claim 11, characterized in that it is administered at a daily dose of approximately 2 mg / kg to 2 μg / kg of body weight.   13. Pharmaceutical composition characterized in that it contains in a suitable vehicle, for enteral, parenteral, topical or ocular administration, at least one compound of formula (1)   according to any one of claims 1 to 10.   14. A composition according to claim 13 characterized in that it is in a form suitable for topical application and   contains from 0.0005 to about 5% by weight of compound-formula (I).   15. Use of a compound of formula (I) according to any one   Claims 1 to 10 for the preparation of a pharmaceutical composition   intended for the treatment of dermatological, rheumatic, respiratory conditions as well as ophthalmological.   16. Cosmetic composition for body and hair hygiene characterized in that it contains, in a suitable cosmetic vehicle, at least one compound of formula (I) according to any one of Claims I to 10. - 47 - - 47 2570377   17. Cosmetic composition according to claim 16, characterized in that it contains the compound of formula (I) at a concentration of   between 0.0005 and 2% and preferably between 0.01 and 1% by weight.